Mutations of the p53 gene are found in over 50% of human tumors, highlighting the importance of p53 in tumor suppression.
Numerous studies have reported on the interactions between p53, IGF-1-AKT and mTOR pathways as potentially explaining some of the tumor suppressive activities of p53. To further understand the basis of these interactions, we analyzed the involvement of DJ-1, an oncogene known to drive AKT-mediated cell survival, in the p53-AKT axis.
In this study, we show that DJ-1 and p53 are tightly 'linked': p53 prevents the accumulation of DJ-1 protein, whereas loss of p53 leads to stabilization and enhancement of DJ-1 expression. Interestingly, this increase in DJ-1 level is only observed when p53 loss is accompanied by transformation of cells. Moreover, DJ-1 seems to be required for the enhanced activation of AKT observed in p53-deficient cells.
Such observation confers a new property to DJ-1 associated to transforming-process to its oncogenic ability to drive AKT activation.
We also show that DJ-1 is necessary for p53 activation following oxidative stress, suggesting the existence of a finely regulated loop between these two proteins in transformed cells. Finally, we demonstrate that in the absence of p53, DJ-1 is stabilized by ROS accumulation, and surprisingly seems to be required for this high intracellular ROS production.
These data offer new insights into the regulation of DJ-1 and suggest that DJ-1 is a target of p53. Importantly, our study highlights that during transformation, DJ-1 is having a key role in the p53-regulated AKT pathway and p53-driven oxidative-stress response.
Institut National de la Santé et de la Recherche Médicale Unité 624, Marseille, France.
Oncogene. 2012 Feb;31(5):664-70
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